Conclusions Although gender may not be predictive of mortality among all infections,
women appear to be at increased risk for death from hospital-acquired pneumonia,
even after controlling for other comorbidities.

Disparity in diagnosis, treatment, and outcome between men and women
among many disease processes has garnered increasing interest over the past
decade, and gender-dependent differences in outcome and quality of care have
been acknowledged by the American Medical Association's Council on Ethical
and Judicial Affairs and others as requiring prudent investigation.1,2 Part of the impetus for examination
of gender differences over a broad range of diagnoses stems from reports of
increased mortality in women with ischemic cardiac disease.3- 7
Studies of other cohorts have demonstrated mixed results regarding gender
inequality in outcome. In initial reports of patients who were mechanically
ventilated, for example, mortality was not affected by gender,8
while a more recent study found being female to be independently associated
with hospital mortality in a similar population.9
However, men with cirrhosis undergoing surgery appear to have a higher complication
rate than women with cirrhosis.10

Among hospitalized and critically ill patients, infections remain a
leading cause of morbidity and mortality, prompting efforts to identify risk
factors for their development and subsequent outcome. The effect of gender
under these circumstances remains unclear. In animal studies, female mice
tolerate polymicrobial sepsis better than males,11
and survival was improved in males after either testosterone receptor blockade12 or dihydroepiandrosterone13
(an inactive metabolite of testosterone) under similar conditions. Clinically,
male gender is an independent risk factor for the development of nosocomial
bloodstream infection,14 and has been associated
with in-hospital mortality in septic surgical patients.15
On the other hand, female gender is found to be an independent predictor of
mortality in patients with Enterococcus bloodstream
infections.16 Women, in addition, may have
a higher mortality among patients with necrotizing soft tissue infection17 and a higher rate of multisystem organ dysfunction
in postoperative cardiac patients developing nosocomial infections.18 Among specific sites of infection, a retrospective
study of 62 patients with nosocomial pneumonia demonstrated no difference
in crude mortality for men vs women,19 and
a separate study of surgical patients with pulmonary infiltrates showed no
difference in mortality after multivariate analysis,20
both despite the reported association between gender and death during mechanical
ventilation.9 A large cohort of hospitalized
patients older than 65 years demonstrated no gender differences in outcomes
for multiple diagnoses including pneumonia.21

These conflicting reports prompted our analysis of surgical patients
to identify gender-related differences in infection-associated outcome, with
an initial hypothesis that among a large number of hospitalized patients,
overall mortality would not be associated with gender after controlling for
other relevant variables.

METHODS

The study was approved by the University of Virginia Human Investigation
Committee and conducted at the University of Virginia Health Sciences Center
Hospital from December 1996 through January 1999. Given the nature of this
observational study, the Human Investigation Committee guidelines did not
require acquisition of informed consent. All patients in the adult general
surgery, trauma, and transplantation units were evaluated prospectively by
the investigators every other day. Infections were initially diagnosed by
the ward staff, but were entered into the study by the investigators only
if they met the study definitions. Patients were identified by every other
day chart review, review of daily microbiologic and laboratory data, antibiotic
use, and attending physician interview. All patients with infections meeting
criteria during the study period were included.

Pulmonary infection was diagnosed when a predominant organism was isolated
from appropriately obtained cultures in the setting of purulent sputum production
and a new or changing infiltrate on chest x-ray with systemic evidence of
infection. Bloodstream infections were diagnosed by isolation of organisms
from blood cultures from any site, with the exception of Staphylococcus epidermidis or other coagulase-negative staphylococci,
which required isolation from 2 sites. Criteria for urinary tract infections
included isolation of more than 105 organisms per milliliter of
urine or more than 104 organisms per milliliter of urine and dysuria.
Criteria for catheter-related infection included isolation of 15 or more colony-forming
units from catheter tips by semiquantitative roll plate technique in the setting
of suspected infection (systemic symptoms or localized purulence). Cellulitis,
peritoneal infections, and surgical site infections were diagnosed clinically,
frequently without obtaining cultures. Treatment generally consisted of the
initiation of nonprophylactic antibiotic therapy, but also included open or
percutaneous drainage of infection without antibiotics (eg, surgical site
infection). Nosocomial infections were those occurring in patients admitted
without evidence of infection at the diagnosed site. Episodes of infection
occurring more than 72 hours apart in the same patient were considered separately
and individually for analysis.

The primary outcome variable was death prior to discharge. Secondary
outcome variables included length of stay after initiation of therapy for
infection, time from initiation of treatment to defervescence (maximum temperature
<38°C for 24 consecutive hours), and time to reduction of white blood
cell (WBC) count to 11 × 109/L or less in patients with initial
significant fever (oral, rectal, or core temperature ≥38.5°C) or leukocytosis
(WBC ≥15 × 109/L). Intake variables included gender, age,
WBC count, maximum temperature, the Acute Physiology and Chronic Health Evaluation
II (APACHE II) score,22 the Acute Physiology
score,22 and time from hospital admission to
initiation of treatment for the infection. The WBC count, maximum temperature,
APACHE II score, and Acute Physiology scores were all the maximal value within
24 hours of initiation of treatment for infection. Other parameters recorded
included infection site, culture data, antibiotic regimen, total duration
of treatment, and the presence of significant comorbidities including diabetes
mellitus (either type), chronic renal insufficiency defined as a documented
serum creatinine level of 176.8 µmol/L (2.0 mg/dL) or more prior to
admission, mechanical ventilation, coexisting malignancy, requirement for
hemodialysis, steroid or other immunosuppressive therapy, administration of
nonautologous blood transfusion during hospitalization but prior to diagnosis
of infection, and presence of a solid organ transplantation. Mechanical ventilation
was defined as the requirement for ventilatory support prior to initiation
of treatment for infection. Routine mechanical ventilation in the immediate
perioperative period was excluded. Significant steroid treatment included
both chronic low-dose and acute high-dose therapy, as defined by APACHE II.22

All univariate comparisons were unpaired and all tests of significance
were 2-tailed. For univariate analysis, continuous variables were compared
by t test with equal or unequal variance as determined
by F test analysis of each parameter. Categorical data were compared using χ2 or Fisher exact test, depending on sample size. All values are expressed
as mean (SE) (continuous variables) or as a percentage of the group from which
they were derived (categorical variables). On univariate analysis, P≤.05 was considered significant. An initial comparison of demographic
data, severity of illness, frequency of comorbidities, and outcome variables
between men and women with infection was followed by a specific comparison
of gender differences for site-specific infections such as pneumonia. Logistic
regression was subsequently performed to identify independent risk factors
for mortality associated with all infections and pneumonia. Since the duration
of hospitalization for nosocomial infections prior to infection was not a
normally distributed variable, we categorized episodes as occurring 0 to 7
days or more than 7 days after admission. Backward stepwise logistic regression
analysis was used to estimate the odds ratio of inpatient mortality (dependent
variable) and the presence of comorbidities or potential prognostic factors
(independent variables). The odds ratio was estimated using the final logistic
regression model as exponential [β-coefficient] and the 95% confidence
intervals for the odds ratio were calculated. An initial Pearson correlation
coefficient was determined for all continuous variables to screen for highly
correlated parameters. Since APACHE II and Acute Physiology scores were highly
correlated, only the APACHE II score was included in the model. After establishing
the logistic regression model and identifying factors significantly associated
with mortality, gender was added to the models to identify its role as an
independent predictor of mortality. Statistical analysis was performed using
SAS software (SAS Institute Inc, Cary, NC) and the assistance of the University
of Virginia Division of Statistics.

RESULTS

Among 1470 total infectious episodes occurring in 892 patients, 782
(53.2%) were in men, and 688 (46.8%) were in women. A univariate comparison
of age, severity of illness, comorbidities, and outcome variables for all
infections is included in Table 1.
Although there was a trend toward increased crude mortality for women, men
had a longer length of stay despite similar severity of illness. Women were
slightly older and were more likely to have had diabetes prior to infection.
Men were more likely to have been transfused or mechanically ventilated and
had a longer interval from admission to initiation of treatment.

A univariate analysis of factors associated with death from all infections
is shown in Table 2. Overall mortality
for men was 11.1%; for women, 14.2%. Since female gender showed a nonsignificant
association with mortality (P = .07), logistic regression
was performed (Table 3). Death
was independently associated with APACHE II score, increasing age, previous
blood transfusion, hospitalization more than 7 days prior to treatment for
infection, and a lower maximum temperature at time of diagnosis, but not gender.

Additional univariate analyses were performed to identify potential
gender-related differences in subcategories of patients felt to be at increased
risk of death. Among 291 critically ill patients with APACHE II scores of
20 or more, 142 (48.8%) were men and 149 (51.2%) were women, with no difference
in either mortality (men, 34.5% vs women, 38.3%; P
= .51) or length of stay expressed as mean (SE) (men, 34 [3] days vs women,
30 [2] days; P = .32). Of 363 infections diagnosed
in the intensive care unit, 210 (57.9%) occurred in men and 153 (42.1%) in
women. There was no difference in mortality (men, 30.0% vs women, 36.6%; P = .19), although the hospital stay was longer for men
(men, 40 [3] days vs women, 30 [2] days; P = .003).
Among 526 (53.2%) men and 462 (46.8%) women with nosocomial infections, there
was no difference in mortality (men, 15.6% vs women, 19.0%; P = .19), although the overall length of stay was higher for men (men,
23 [1] days vs women, 19 [1] days; P = .02). Mortality
for the 163 men and 107 women ventilated at the time of diagnosis was similar
(men, 30% vs women, 36%; P = .30).

Table 4 gives the number
of infections by site and gender and the associated mortality. Pneumonia and
bloodstream infections were more common in men, while urinary tract infections
were more common in women. Mortality was significantly higher for women with
pneumonia or soft tissue infections. Infected sites identified concurrently
with the 267 episodes of bacteremia or fungemia included lung, 24%; catheter,
16%; urinary tract, 15%; peritoneum, 11%; surgical site, 5%; and other, 6%.
Another 25% of bloodstream infections occurred without any identifiable primary
source. Men accounted for 159 (59.6%) and women 108 (40.4%) of these patients,
without a difference in overall mortality (men, 18.2% vs women, 20.4%; P = .66) or length of stay (men, 28 [3] days vs women,
27 [3] days; P = .93). There were no statistically
significant differences in outcomes following urinary tract infections.

Univariate comparisons of 205 men and 121 women with pneumonia are given
in Table 5. Of all pneumonia cases,
94% were hospital-acquired with no difference between men and women. The previously
noted increase in mortality among females occurred despite similar severity
of illness, age, time from admission to initiation of treatment, and overall
duration of treatment. Length of stay was longer for men, but was not attributable
to early deaths among women, since the time to discharge after intervention
for men was similar for survivors and nonsurvivors (28 [2] days vs 28 [5]
days), as it was for female survivors and nonsurvivors (23 [2] days vs 21
[3] days). The mortality for ventilator-associated pneumonia was 23.2% for
men and 40.8% for women (P = .03) while the mortality
for nonventilator-associated pneumonia was 13.3% and 28.6% for men and women,
respectively (P = .01). Among all causative organisms
in pneumonia, gram-positive organisms accounted for 25% and 20% (P = .26), gram-negative organisms for 43% and 44% (P = .81), Staphylococcus aureus for 16% and
14% (P = .50), and Pseudomonas
aeruginosa for 9% and 13% (P = .09) in men
and women, respectively. Men with pneumonia received more penicillin derivatives
as a proportion of all antibiotics used (38.7% vs 16.7%; P = .02), although there were no differences in the proportional use
of any other antibiotic class (eg, cephalosporins, aminoglycosides, fluoroquinolones,
vancomycin, or carbapenems), and mortality for pneumonia treated with penicillins
was similar to that in the group treated with other agents (data not shown).
Time from fever (≥38.5°C) to initiation of therapy among febrile men
and women was similar (men, 20 [1] hours vs women, 23 [3] hours; P = .29).

Previous clinical and experimental studies examining gender-related
differences in infectious complications and mortality have provided inconsistent
results. Our study of a large cohort of hospitalized surgical patients shows
that gender is not a strong independent predictor of outcome when examining
all infections. The in-hospital mortality for women with pneumonia, however,
was almost twice that of men, and was still significantly increased after
controlling for multiple other comorbid factors. Interestingly, there was
also an increased mortality for women with soft tissue infection as previously
described,17 although the sample size was inadequate
to perform meaningful logistic regression analysis.

Despite sparse data in the recent literature regarding the specific
relationship between gender and outcome in hospital-acquired pneumonia, some
studies provide for an indirect comparison of these findings. Kollef et al9 have recently shown that female gender independently
predicts mortality in a multivariate analysis of a large cohort of patients
who were mechanically ventilated. Although we did not see increased mortality
during our study in female patients who were mechanically ventilated, their
study differed in that less than 5% of their patients had a diagnosis of pneumonia.
Rello et al19 found no difference in pneumonia-associated
mortality between men and women, although that study was smaller (62 patients)
and had a higher overall mortality (60%), suggesting either a more rigorous
definition of pneumonia or later diagnosis. Singh et al20
also found that gender was not predictive of mortality among a cohort of 129
surgical patients with pulmonary infiltrates, although only 14% of patients
were women and pneumonia accounted for only 30% of the pulmonary infiltrates.

Many of the concerns regarding gender disparity in ischemic cardiac
disease originated from reported delays in the time from presentation to definitive
treatment and decreases in the use of hospital resources for women.4,5 Our study demonstrated similar time
intervals from admission to initiation of treatment among male and female
patients with pneumonia, as well as time from fever to initiation of treatment.
Although these are indirect measures of the physician's timeliness of administration
of care, they do support a relatively similar approach to male and female
patients with infection. The comparable efficiency of initiation of treatment,
in addition to similar length of treatment and antibiotic use between genders,
minimizes the likelihood that women received a worse process of care. Consistent
with our findings, Pearson et al21 reported
comparable objective measures of quality of care between men and women initially
hospitalized with pneumonia.

One additional issue regarding the disparate outcome with pneumonia
is the potential for intrinsic gender differences in the pathogenesis of disease
and in the host's response to infection. Clinical series examining gender
disparity in the host response to infection are scarce, although recent studies
in the transplantation literature have alluded to hormonal and/or immunological
diversity that may affect outcome in critically ill patients.23,24
Experimentally, survival from polymicrobial sepsis has been found to be highly
gender-dependent, and presumably hormone-dependent in rodents.11- 13
Among patients in the current study with pneumonia, women did have a higher
WBC count and slightly lower temperature at time of diagnosis, perhaps suggesting
a small gender-dependent difference in the physiologic response to infection.
This finding, however, may alternatively represent a difference in disease
progression in women related to a delay in diagnosis. In terms of response
to treatment, the time interval from initiation of treatment to normalization
of temperature and WBC count was similar between men and women. Making a large
difference in phenotypic response between men and women remains unlikely.
One additional etiologic factor is related to respiratory tract colonization
in critically ill hospitalized patients. Although oropharyngeal colonization
was not assessed in this study, gender differences in skin colonization leading
to subsequent catheter-related infections have been reported.25

We found that despite similar severity of illness and length of treatment
and a slightly younger mean age, infected men were hospitalized longer following
initiation of treatment for infection. A similar increase in length of stay
was also observed in male patients developing pneumonia, a trend noted for
both survivors and nonsurvivors. Compared with the mortality data, these seemingly
contradictory findings may be related to a large subset of predominantly male
trauma patients requiring prolonged inpatient management and rehabilitation
without significant increases in the acute severity of illness scores. Because
the duration of therapy was similar between genders, the increased length
of stay most likely is attributable to post-treatment hospitalization, again
implying causation more related to underlying diseases than the largely nosocomial
infections studied here.

Identification of alterable factors that can significantly affect outcomes
among patients with infections, particularly hospital-acquired pneumonia,
remains a difficult task. The unique association between female gender and
pneumonia-associated mortality suggests the need for further investigation
of characteristics of presentation of disease, administration of care, pathogenesis
of infection, and host response to address potential gender differences in
infection-associated outcome. A detailed understanding of any such disparity
between men and women may provide valuable information for improving interventions
and outcomes in all infected patients.